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Nephropathy is one of the main features of Fabry disease (FD) that leads, in untreated patients with classical mutations, to end-stage renal disease (ESRD) from the third to the fifth decade of life. The availability of a specific treatment modified the natural history of FD; in particular, it was widely reported that enzyme replacement therapy (ERT) is able to slow the progression of the disease. Regarding Fabry nephropathy, several reports have documented an elevated estimated glomerular filtration rate (eGFR) slope in untreated patients as expression of a rapid disease progression towards ESRD. Otherwise, the prompt start of treatment may be beneficial in stabilizing renal function or slowing its decline. Therefore, based on data in the literature about the effects of ERT on eGFR decline and on the evidence supporting the role of eGFR slope as a surrogate endpoint for chronic kidney disease progression, we suggest, in this 'Expert Opinion', that a treatment should be defined effective when eGFR decline is <1 ml/min/1.73 m2/year and not effective when eGFR loss remains ≥3 ml/min/1.73 m2/year (≥2.5 ml/min/1.73 m2/year in females). Moreover, practical clinical recommendations and guidance for Fabry patients suggests that a change in treatment may be appropriate if individualized therapeutic goals are not achieved. Since a dose-dependent efficacy has been demonstrated for ERT, we suggest considering a switch to a higher dose of ERT in symptomatic adult Fabry patients (ages 18–60 years) with an eGFR of 45–90 ml/min/1.73 m2 and treated with a stable dose of ERT for at least 1 year, in which a linear negative slope of eGFR of 3 ml/min/1.73 m2/year for males (2.5 ml/min/1.73 m2/year for females) was observed. [ABSTRACT FROM AUTHOR]

Background: Infection of Cardiac Implantable Electronic Devices (CIEDI) is a real public health problem. The main aim of this study was to determine the diagnostic performance of 18F-FDG PET/CT in the diagnosis of CIEDI. Methods: A total of 48 patients, who performed 18F-FDG PET/CT for the clinical suspicion of CIEDI were retrospectively analyzed; all patients were provided with a model with procedural recommendations before the exam. Sensitivity (Se), specificity (Sp), positive predictive value (PPV), negative predictive value (NPV) and diagnostic accuracy (DA) of 18F-FDG PET/CT were calculated; the reproducibility of qualitative analysis was assessed with Cohen's κ test. The semi-quantitative parameters (SUVmax, SQR and TBR) were evaluated in CIEDI+ and CIEDI− patients using the Student' t-test; ROC curves were elaborated to detect cut-off values. The trend of image quality with regards to procedural recommendation adherence was evaluated. Results: Se, Sp, PPV, NPV and DA were respectively 96.2%, 81.8%, 86.2%, 94.7% and 89.6%. The reproducibility of qualitative analysis was excellent (K = 0.89). Semiquantitative parameters resulted statistically different in CIEDI+ and CIEDI− patients. Cut-off values were SUVmax = 2.625, SQR = 3.766 and TBR = 1.29. Trend curves showed increasing image quality due to adherence to procedural recommendations. Conclusions: 18F-FDG-PET/CT is a valid tool in the management of patients suspected of CIEDI and adherence to procedural recommendations improves its image quality. [ABSTRACT FROM AUTHOR]

Different insights into the connection between kidney [18F]fluorodesoxyglucose ([18F]FDG) uptake at positron emission tomography/computed tomography (PET/CT) and renal function have been proposed in the past. The aim of this study was therefore to assess the presence of a correlation between these two parameters. Kidney uptakes were assessed and compared to the creatinine (Cr) values and estimated glomerular filtration rate (EGFR) among different classes of renal functional impairment or kidney status. A total of 339 patients and 385 different PET/CT scans were included in this study. Significant correlations between kidney uptakes and renal function parameters were reported in most of the groups studied, with the exception of patients with Cr < 1.2 mg/dL and subjects with a kidney transplantation. Strong concordance in the assessment of renal parenchymal uptakes between the different readers was reported. To conclude, strong correlations for renal [18F]FDG uptake with Cr levels and the EGFR were reported, with the exception of the group of patients with a Cr value < 1.2 mg/dL and for the group with a kidney transplantation. [ABSTRACT FROM AUTHOR]

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma worldwide. After first-line therapy, 30–40% of patients relapse or experiment with refractory disease. 18F-FDG PET/CT represents a validated diagnostic tool in post-treatment evaluation of FDG-avid lymphoma, and the Deauville Score (DS), a five-point visual scale, is usually used to assess response. However, the increased number of false positive findings suggested the need to search for new parameters. The aim of this study is to evaluate the prognostic value of End-of-Treatment-PET, comparing DS to the semi-quantitative Lesion-to-Liver ratio (LLR). Methods: newly diagnosed DLBCL patients who underwent 18F-FDG PET/CT were retrospectively analyzed. End-of-Treatment PET findings were assessed first using DS; secondly, assigned the LLR. Results: a total of 105 patients were finally enrolled. ROC analysis showed an LLR of 1.80 as the optimal cutoff value for predicting a disease progression (sensitivity 58%, specificity 95%). Both DS and LLR showed a statistically significant correlation with PFS and OS. LLR resulted in a better diagnostic performance than DS. Conclusions: LLR showed to be a reliable diagnostic method to assess treatment response in DLBCL. The integration of visual and semi-quantitative criteria could help in decision making, improving specificity and PPV. [ABSTRACT FROM AUTHOR]

Transcranial direct current stimulation (tDCS) has been used to reduce pain in range of chronic pain states. The aim of this review is to evaluate the effectiveness of tDCS on pain reduction and related disability in patients with non-specific chronic low back pain (CLBP). A computer-based systematic literature search was performed in five databases according to PRISMA guidelines. Randomized controlled trials (RCTs) that assessed the effects of tDCS on pain and related disability in patients with non-specific CLBP were included. Modified Jadad scale and Cochrane's risk of bias assessment were used to determine the studies' quality and risk of bias. Meta-analyses were performed by calculating the standardized mean difference (SMD) at 95% confidence interval (CI). Nine RCTs (411 participants) were included in the systematic review according to inclusion criteria, while only five studies could be included in the meta-analysis. The primary motor cortex (M1) was the main stimulated target. The meta-analysis showed non-significant effect of multiple sessions of tDCS over M1 on pain reduction and disability post-treatment respectively, (SMD = 0.378; 95% CI = − 0.264–1.020; P = 0.249), (SMD = 0.143; 95% CI = − 0.214–0.499; P = 0.434). No significant adverse events were reported. The current results do not support the clinical use of tDCS for the reduction of pain and related disability in non-specific CLBP. However, the limited number of available evidence limits our conclusions on the effectiveness of these approaches. [ABSTRACT FROM AUTHOR]

Abstract Background and aim In autosomal dominant polycystic kidney disease (ADPKD) cardiac abnormalities have been observed before the onset of hypertension or renal dysfunction. We sought to characterize, in ADPKD patients, left ventricular (LV) function and its changes after somatostatin-analogue octreotide-LAR treatment. Methods In a 1:1:1 cross-sectional study, we evaluated LV function by speckle-tracking echocardiography in 34 ADPKD patients from one ALADIN-trial center and in 34 age- and gender-matched healthy controls and 34 equally-matched renal controls with non-cystic chronic kidney disease. Changes in LV function were compared in the 16 and 18 ADPKD patients originally randomized to 3 year-treatment with octreotide-LAR or placebo, respectively. Results LV twist and untwisting rates were lower in ADPKD patients that in healthy or renal controls (6.1 ± 2.6° vs. 11.1 ± 2.1° and 10.2 ± 3.7°; −49.5 ± 18.1°/s vs. −79.8 ± 12.2°/s and −84.3 ± 25.9°/s, respectively, all p < 0.001). The correlation between LV mass or diastolic BP and untwisting rate was positive in ADPKD patients (r = 0.38, p = 0.025 and r = 0.44, p = 0.011, respectively), not significant in healthy controls and negative in renal controls (r = −0.38; p = 0.023 and r = −0.40, p = 0.012, respectively. LV untwisting rate improved from −49.9 ± 18.6°/s to −70.3 ± 27.5°/s with octreotide-LAR, but did not change with placebo (p = 0.027 for treatment effect). At adjusted linear regression analysis, octreotide-LAR therapy emerged as the only independent predictor of untwisting rate improvement at final visit [beta coefficient −0.504 (95% CI −46.905–−6.367), p = 0.014]. Conclusions In ADPKD patients LV function is early impaired. Somatostatin-analogue therapy might help in preventing or ameliorating LV dysfunction in this population. Clinical Trial Registration http://www.clinicaltrials.gov , NCT0030928. Highlights • In ADPKD patients LV function is impaired trough disease-specific mechanisms. • Treatment with octreotide-LAR, a somatostatin analogue, is able to preserve LV function in these patients. • Indications of somatostatin-analogue therapy might be broadened to cardiovascular risk amelioration. [ABSTRACT FROM AUTHOR]

Background. Fabry's disease (FD) is a rare, multi-organ lysosomal disease, caused by the deficiency of the enzyme a-galactosidase A, and is difficult to diagnose. Although parapelvic cysts (PC) were previously associated with FD, their prevalence and significance are unclear. Methods. The present study aimed to: (i) evaluate, by renal ultrasound, the real prevalence of PC and of their determinants in a multicentre, nationwide cohort of FD patients (n = 173, Study 1) and (ii) ascertain whether a greater accuracy of PC detection improved their identification, in FD patients from a single centre (n = 67, Study 2). In both studies, for each FD patient, an age- and renal function-matched subject was selected for comparison (1:1). Results. In Study 1, PC were detected in 28.9% of FD subjects and in only 1.1% of control subjects (P<0.001). The presence of other renal abnormalities did not differ between the groups, nor differences exist in the main demographic and laboratory parameters between the groups. In Study 2, the greater accuracy of ultrasound increased PC prevalence from 29.8% to 43.3% in the same subjects (P<0.05). In both studies, no correlation was detected between PC and the main demographic, clinical and biochemical parameters, including use of enzyme replacement therapy (P<0.1, minimum value). Finally, no difference existed between FD patients with and without PC. Conclusions. The present study suggests that the presence of PC in renal patients should alert physicians to consider the diagnosis of FD, primarily in subjects with an unclear family history of renal disease and in the presence of other stigmata of the disease. [ABSTRACT FROM AUTHOR]

Hyperammonemia in urea cycle disorders: role of the nephrologist Severe hyperammoniemia denotes a clinical condition associated with high blood ammonia levels and uncertain prognosis. The presentation can vary with the age of the patent and the magnitude of the increase in blood ammonia levels. Persistent hyperammonemia, if not treated rapidly, may cause irreversible neuronal damage. The aim of therapy should be to normalize blood ammonia levels. Recent experience has provided treatment guidelines that include minimizing endogenous ammonia production and protein catabolism, restricting nitrogen intake, administering substrates of the urea cycle, administering compounds that facilitate the removal of ammonia through alternative pathways, and, in severe cases, dialysis therapy. Hemodialysis is the most effective treatment for rapidly reducing blood ammonia levels. Continuous hemofiltraton and peritoneal dialysis are also effective modalities to reduce blood ammonia levels. An improved understanding of the metabolism of ammonia and clinical consequences of hyperammonemia will assist the nephrologist in providing optimal care for this high-risk patent population. [ABSTRACT FROM AUTHOR]

Background: The beneficial effects of dietary restriction of proteins in chronic kidney disease are widely recognized; however, poor compliance to prescribed low-protein diets (LPD) may limit their effectiveness. To help patients to adhere to the dietary prescriptions, interventions as education programmes and dietary counselling are critical, but it is also important to develop simple and attractive approaches to the LPD, especially when dietitians are not available. Therefore, we elaborated a simplified and easy to manage dietary approach consisting of 6 tips (6-tip diet, 6-TD) which could replace the standard, non-individualized LPD in Nephrology Units where dietary counselling is not available; hence, our working hypothesis was to evaluate the effects of such diet vs a standard moderately protein-restricted diet on metabolic parameters and patients' adherence. Methods: In this randomized trial, 57 CKD patients stage 3b-5 were randomly assigned (1:1) to receive the 6-TD (Group 6-TD) or a LPD containing 0.8 g/kg/day of proteins (Group LPD) for 6 months. The primary endpoint was to evaluate the effects of the two different diets on the main 'metabolic' parameters and on patients' adherence (registration number NCT01865526). Results: Both dietary regimens were associated with a progressive reduction in protein intake and urinary urea excretion compared to baseline, although the decrease was more pronounced in Group 6-TD. Effects on serum levels of urea nitrogen and urinary phosphate excretion were greater in Group 6-TD. Plasma levels of phosphate, bicarbonate and PTH, and urinary NaCl excretion remained stable in both groups throughout the study. 44 % of LPD patients were adherent to the dietary prescription vs 70 % of Group 6-TD. Conclusions: A simplified diet, consisting of 6 clear points easily managed by CKD patients, produced beneficial effects either on the metabolic profile of renal disease and on patients' adherence to the dietary plan, when compared to a standard LPD. [ABSTRACT FROM AUTHOR]

Background: We present the case of a white 35-year-old male with a diagnosis of Fabry disease and negative family history. Case presentation: At the age of 31, he underwent a renal biopsy with a diagnosis of hypertension-induced nephroangiosclerosis. At the age of 35, he was referred to our hospital and started dialysis: the unusual finding of left ventricular hypertrophy with a normal ejection fraction and of myocardial fibrosis at the cardiac magnetic resonance suggested a diagnosis of Fabry disease, although there was no apparent family history—so extensive tests were subsequently undertaken. The patient had low plasma levels of a-galactosidase A and the genetic analysis showed a single nucleotide point mutation in hemizygosis at nucleotide c.901 C>T in exon 6 of the GLA gene, confirming the diagnosis of Fabry disease. We extended the genetic analysis to all family members of the patient (mother, sister and brothers) and none of them had any alteration in the GLA gene, suggesting a de novo mutation in the patient. Conclusions: In a family, it is rare to find only one Fabry disease affected subject with a de novo mutation. These findings emphasize the importance of early diagnosis, genetic counseling and studying the genealogical tree of suspicious patients, even in absence of a typical family history. [ABSTRACT FROM AUTHOR]

Background. Proteinuria is the predominant risk factor for renal disease progression in Fabry disease (FD). When urine protein excretion is controlled to <0.50 g/24 h, the rate loss of glomerular filtration rate (GFR) is not significantly different from 0. However, enzyme replacement therapy (ERT) alone does not decrease proteinuria and it has been recommended that patients receiving ERT also receive anti-renin-angiotensin system (RAS) therapy. Emerging evidence show that paricalcitol (PCT) reduces proteinuria in the presence of intensified inhibition of RAS; however, there is no evidence in FD. We evaluated the antiproteinuric effect of PCT in FD patients with proteinuria >0.50 g/24 h persisting despite ERT and anti-RAS therapy titrated to maximum tolerated dosage. Methods. Fifteen FD patients were selected and studied in the first 6 months of add-on oral PCT (1 µg/day) and, in order to verify the dependence of proteinuria reduction on PCT, 3 months after drug withdrawal. Results. At baseline, proteinuria was 1.3 ± 0.6 g/24 h. Six months of add-on PCT significantly decreased proteinuria to 0.4 ± 0.3 g/24 h, with levels <0.50 g/24 h achieved in four patients at Month 1, six at Month 3, and in 12 by Month 6, in the absence of changes to BP and GFR. Proteinuria recovered to basal value after drug withdrawal. Conclusions. In conclusion, our study is the first evidence that PCT is effective in reducing proteinuria in FD patients in the presence of ERT and anti-RAS therapy. [ABSTRACT FROM AUTHOR]

Introduction. Iron deficiency is a common cause of anaemia in non-dialysis chronic kidney disease (ND-CKD). Controversies exist about the optimal route of administration for iron therapy. Liposomal iron, a new generation oral iron with high gastrointestinal absorption and bioavailability and a low incidence of side effects, seems to be a promising new strategy of iron replacement. Therefore, we conducted a study to determine whether liposomal iron, compared with intravenous (IV) iron, improves anaemia in ND-CKD patients. Methods. In this randomized, open-label trial, 99 patients with CKD (stage 3-5, not on dialysis) and iron deficiency anaemia [haemoglobin (Hb) ≤12 g/dL, ferritin ≤100 ng/mL, transferrin saturation ≤25%] were assigned (2:1) to receive oral liposomal iron (30 mg/day, Group OS) or a total dose of 1000 mg of IV iron gluconate (125 mg infused weekly) (Group IV) for 3 months. The patients were followed-up for the treatment period and 1 month after drug withdrawal. The primary end point was to evaluate the effects of the two treatments on Hb levels; the iron status, compliance and adverse effects were also evaluated. Results. The short-term therapy with IV iron produced a more rapid Hb increase compared with liposomal iron, although the final increase in Hb was similar with either treatment; the difference between the groups was statistically significant at the first month and such difference disappeared at the end of treatment. After iron withdrawal, Hb concentrations remained stable in Group IV, while recovered to baseline in the OS group. The replenishment of iron stores was greater in the IV group. The incidence of adverse event was significantly lower in the oral group (P < 0.001), and the adherence was similar in the two groups. Conclusions. Our study shows that oral liposomal iron is a safe and efficacious alternative to IV iron gluconate to correct anaemia in ND-CKD patients, although its effects on repletion of iron stores and on stability of Hb after drug discontinuation are lower. [ABSTRACT FROM AUTHOR]

Background: Contrast media (CM)-induced nephropathy (CIN) is an acute deterioration of renal function following administration of CM mediated to a large extent by the increased production of ROS within the kidney. Aim of this study was to evaluate whether a novel isoform of a recombinant Manganese SOD (rMnSOD) could provide an effective protection against CIN; this molecule shares the same ability of physiological SODs in scavenging reactive oxygen species (ROS) but, due to its peculiar properties, enters inside the cells after its administration. Methods: We studied the effects rMnSOD on oxidative damage in a rat model of CIN in uninephrectomized rats, that were randomly assigned to 3 experimental Groups: Group CON, control rats treated with the vehicle of CM, Group HCM, rats treated with CM and Group SOD, rats treated with CM and rMnSOD. Results: In normal rats, pretreatment with rMnSOD, reduced renal superoxide anion production, induced by the activation of NAPDH oxidase, by 84 % ( p < 0.001). In rats of Group HCM, ROS production was almost doubled compared to rat of Group CON ( p < 0.01) but returned to normal values in rats of Group SOD, where a significant increase of SOD activity was detected (+16 % vs HCM, p < 0.05). Administration of CM determined a striking fall of GFR in rats of Group HCM (−70 %, p < 0.001 vs CON), greatly blunted in Group SOD (−28 % vs CON, p < 0.01); this was associated with a lower presence of both tubular necrosis and intratubular casts in SOD-treated rats (both p < 0.01 vs Group HCM). Conclusions: Our data indicate that rMnSOD is able to reduce renal oxidative stress, thus preventing the reduction of GFR and the renal histologic damage that follows CM administration. [ABSTRACT FROM AUTHOR]

In vitro and in vivo studies have demonstrated enhanced hypoxia and formation of reactive oxygen species (ROS) in the kidney following the administration of iodinated contrast media, which play a relevant role in the development of contrast media-induced nephropathy. Many studies indeed support this possibility, suggesting a protective effect of ROS scavenging or reduced ROS formation with the administration of N-acetylcysteine and bicarbonate infusion, respectively. Furthermore, most risk factors, predisposing to contrast-induced nephropathy, are prone to enhanced renal parenchymal hypoxia and ROS formation. In this review, the association of renal hypoxia and ROS-mediated injury is outlined. Generated during contrast-induced renal parenchymal hypoxia, ROS may exert direct tubular and vascular endothelial injury and might further intensify renal parenchymal hypoxia by virtue of endothelial dysfunction and dysregulation of tubular transport. Preventive strategies conceivably should include inhibition of ROS generation or ROS scavenging. [ABSTRACT FROM AUTHOR]

Abstract: Anderson-Fabry disease is an X-linked lysosomal storage disorder resulting from the deficiency of the hydrolytic enzyme alpha galactosidase A, with consequent accumulation of globotrioasoyl ceramide in cells and tissues of the body, resulting in a multi-system pathology including end organ failure. In the classical phenotype, cardiac failure, renal failure and stroke result in a reduced median life expectancy. The current causal treatment for Fabry disease is the enzyme replacement therapy (ERT): two different products, Replagal (agalsidase alfa) and Fabrazyme (agalsidase beta), have been commercially available in Europe for almost 10years and they are both indicated for long-term treatment. In fact, clinical trials, observational studies and registry data have provided many evidences for safety and efficacy of ERT in improving symptoms of pain, gastrointestinal disturbances, hypohidrosis, left ventricular mass index, glomerular filtration rate and quality of life. Few data are available on comparison of the two treatments and on the clinical course of the disease. This article reviews the published evidence for clinical efficacy of the two available enzyme preparations. [Copyright &y& Elsevier]

Abstract: Work over the past two decades lead to substantial changes in our understanding of dystonia, which was, until recently, considered an exclusively sporadic movement disorder. The discovery of several gene mutations responsible for many inherited forms of dystonia has prompted much effort in the generation of transgenic mouse models bearing mutations found in patients. The large majority of these rodent models do not exhibit overt phenotypic abnormalities, or neuronal loss in specific brain areas. Nevertheless, both subtle motor abnormalities and significant alterations of synaptic plasticity have been recorded in mice, suggestive of an altered basal ganglia circuitry. In addition, robust evidence from experimental and clinical work supports the assumption that dystonia may indeed be considered a disorder linked to the disruption of synaptic “scaling”, with a prevailing facilitation of synaptic potentiation, together with the loss of synaptic inhibitory processes. Notably, neurophysiological studies from patients carrying gene mutations as well as from non-manifesting carriers have shown the presence of synaptic plasticity abnormalities, indicating the presence of specific endophenotypic traits in carriers of the gene mutation. In this survey, we review findings from a broad range of data, obtained both from animal models and human research, and propose that the abnormalities of synaptic plasticity described in mice and humans may be considered an endophenotype to dystonia, and a valid and powerful tool to investigate the pathogenic mechanisms underlying this movement disorder. This article is part of a Special Issue entitled “Advances in dystonia”. [Copyright &y& Elsevier]

Dominantly inherited mutations in leucine-rich repeat kinase 2 (LRRK2) are a common genetic cause of Parkinson's disease (PD). The importance of the R1441 residue in the pathogenesis is highlighted by the identification of three distinct missense mutations. To investigate the pathogenic mechanism underlying LRRK2 dysfunction, we generated a knockin (KI) mouse in which the R1441C mutation is expressed under the control of the endogenous regulatory elements. Homozygous R1441C KI mice appear grossly normal and exhibit no dopaminergic (DA) neurodegeneration or alterations in steady-state levels of striatal dopamine up to 2 years of age. However, these KI mice show reductions in amphetamine (AMPH)-induced locomotor activity and stimulated catecholamine release in cultured chromaffin cells. The introduction of the R1441C mutation also impairs dopamine D2 receptor function, as suggested by decreased responses of KI mice in locomotor activity to the inhibitory effect of a D2 receptor agonist, quinpirole. Furthermore, the firing of nigral neurons in R1441C KI mice show reduced sensitivity to suppression induced by quinpirole, dopamine, or AMPH. Together, our data suggest that the R1441C mutation in LRRK2 impairs stimulated dopamine neurotransmission and D2 receptor function, which may represent pathogenic precursors preceding dopaminergic degeneration in PD brains. [ABSTRACT FROM AUTHOR]

Parkin is the most common causative gene of juvenile and early-onset familial Parkinson’s diseases and is thought to function as an E3 ubiquitin ligase in the ubiquitin-proteasome system. However, it remains unclear how loss of Parkin protein causes dopaminergic dysfunction and nigral neurodegeneration. To investigate the pathogenic mechanism underlying these mutations, we used parkin−/− mice to study its physiological function in the nigrostriatal circuit. Amperometric recordings showed decreases in evoked dopamine release in acute striatal slices of parkin−/− mice and reductions in the total catecholamine release and quantal size in dissociated chromaffin cells derived from parkin−/− mice. Intracellular recordings of striatal medium spiny neurons revealed impairments of long-term depression and long-term potentiation in parkin−/− mice, whereas long-term potentiation was normal in the Schaeffer collateral pathway of the hippocampus. Levels of dopamine receptors and dopamine transporters were normal in the parkin−/− striatum. These results indicate that Parkin is involved in the regulation of evoked dopamine release and striatal synaptic plasticity in the nigrostriatal pathway, and suggest that impairment in evoked dopamine release may represent a common pathophysiological change in recessive parkinsonism. [ABSTRACT FROM AUTHOR]

Abstract: Background: Despite the high prevalence of sleep disorders in patients with kidney disease, no relationship has been demonstrated between sleep quality and the degree of renal function in cross-sectional studies. A prospective trial was, therefore, started in patients with chronic renal failure (CRF) to evaluate whether a link exists between the modifications of these parameters observed during a three-year follow-up period. Methods: Sleep quality was determined by the Pittsburgh Sleep Quality Index (PSQI) at baseline and after two and three years (Time 0, 2 and 3, respectively) in 78 patients with various degrees of CRF in association with the main clinical and biochemical variables. Results: The baseline PSQI averaged 6.2±3.8 (range: 0–21, with higher values indicating worse sleep quality) and was significantly increased at both Time 2 and 3 (8.8±3.7 and 10.2±3.5, respectively, P <0.0001 vs baseline), whereas creatinine clearance progressively decreased (45±24 vs 41±26 and 32±20ml/min, at time 0, 2 and 3, respectively, P <0.0001), although an independent association with PSQI could not be demonstrated after adjustment for confounding factors (P =0.90, mixed linear model). Conclusions: Our data suggest that the progression of renal disease is accompanied by a progressive worsening of sleep quality; age is strongly related to both phenomena. PSQI represents an easy tool to use to detect sleep disorders and to more effectively evaluate renal patients; the prevention of sleep disorders by early and appropriate treatments could beneficially influence the course of the disease. [Copyright &y& Elsevier]

Twenty years ago, striatal cholinergic neurons were central figures in models of basal ganglia function. But since then, they have receded in importance. Recent studies are likely to lead to their re-emergence in our thinking. Cholinergic interneurons have been implicated as key players in the induction of synaptic plasticity and motor learning, as well as in motor dysfunction. In Parkinson''s disease and dystonia, diminished striatal dopaminergic signalling leads to increased release of acetylcholine by interneurons, distorting network function and inducing structural changes that undoubtedly contribute to the symptoms. By contrast, in Huntington''s disease and progressive supranuclear palsy, there is a fall in striatal cholinergic markers. This review gives an overview of these recent experimental and clinical studies, placing them within the context of the pathogenesis of movement disorders. [Copyright &y& Elsevier]

Parkinson's disease (PD) is characterized by the selective vulnerability of the nigrostriatal dopaminergic circuit. Recently, loss-of-function mutations in the PTEN-induced kinase 1 (PINK1) gene have been linked to early-onset PD. How PINK1 deficiency causes dopaminergic dysfunction and degeneration in PD patients is unknown. Here, we investigate the physiological role of PINK1 in the nigrostriatal dopaminergic circuit through the generation and multidisciplinary analysis of PINK1-/- mutant mice. We found that numbers of dopaminergic neurons and levels of striatal dopamine (DA) and DA receptors are unchanged in PINK1-/- mice. Amperometric recordings, however, revealed decreases in evoked DA release in striatal slices and reductions in the quantal size and release frequency of catecholamine in dissociated chromaffin cells. Intracellular recordings of striatal medium spiny neurons, the major dopaminergic target, showed specific impairments of corticostriatal long-term potentiation and long-term depression in PINK1-/- mice. Consistent with a decrease in evoked DA release, these striatal plasticity impairments could be rescued by either DA receptor agonists or agents that increase DA release, such as amphetamine or L-dopa. These results reveal a critical role for PINK1 in DA release and striatal synaptic plasticity in the nigrostriatal circuit and suggest that altered dopaminergic physiology may be a pathogenic precursor to nigrostriatal degeneration. [ABSTRACT FROM AUTHOR]

Abstract: Repetitive stimulation of the corticostriatal pathway can cause either a long-lasting increase, or an enduring decrease in synaptic strength, respectively referred to as long-term potentiation (LTP), and long-term depression (LTD), both requiring a complex sequence of biochemical events. Once established, LTP can be reversed to control levels by a low-frequency stimulation (LFS) protocol, an active phenomenon defined “synaptic depotentiation”, required to erase redundant information. In the 6-hydroxydopamine (6-OHDA) rat model of Parkinson''s disease (PD), striatal synaptic plasticity has been shown to be impaired, though chronic treatment with l-dopa was able to restore it. Interestingly, a consistent number of l-dopa-treated animals developed involuntary movements, resembling human dyskinesias. Strikingly, electrophysiological recordings from the dyskinetic group of rats demonstrated a selective impairment of synaptic depotentiation. This survey will provide an overview of plastic changes occurring at striatal synapses. The potential relevance of these findings in the control of motor function and in the pathogenesis both of Parkinson''s disease and l-dopa-induced motor complications will be discussed. [Copyright &y& Elsevier]

Changing the strength of synaptic connections between neurons is widely assumed to be the mechanism by which memory traces are encoded and stored in the central nervous system. Plastic changes appear to follow a regional specialization and underlie the specific type of memory mediated by the brain area in which plasticity occurs. Thus, long-term changes occurring at excitatory corticostriatal synapses should be critically involved in motor learning. Indeed, repetitive stimulation of the corticostriatal pathway can cause either a long-lasting increase or an enduring decrease in synaptic strength, respectively referred to as long-term potentiation (LTP), and long-term depression, both requiring a complex sequence of biochemical events. Once established, LTP can be reversed to control levels by a low-frequency stimulation protocol, an active phenomenon defined "synaptic depotentiation," required to erase redundant information. In the 6-hydroxydopamine rat model of Parkinson's disease (PD), striatal synaptic plasticity has been shown to be impaired, although chronic treatment with levodopa was able to restore it. Of interest, a consistent number of L-dopa-treated animals developed involuntary movements, resembling human dyskinesias. Strikingly, electrophysiological recordings from the dyskinetic group of rats demonstrated a selective impairment of synaptic depotentiation. This survey will provide an overview of plastic changes occurring at striatal synapses. The potential relevance of these findings in the control of motor function and in the pathogenesis both of PD and L-dopa-induced motor complications will be discussed. [ABSTRACT FROM AUTHOR]

Summary: The manifestations of Parkinson’s disease are caused by reduced dopaminergic innervation of the striatum. Loss-of-function mutations in the DJ-1 gene cause early-onset familial parkinsonism. To investigate a possible role for DJ-1 in the dopaminergic system, we generated a mouse model bearing a germline disruption of DJ-1. Although DJ-1-/- mice had normal numbers of dopaminergic neurons in the substantia nigra, evoked dopamine overflow in the striatum was markedly reduced, primarily as a result of increased reuptake. Nigral neurons lacking DJ-1 were less sensitive to the inhibitory effects of D2 autoreceptor stimulation. Corticostriatal long-term potentiation was normal in medium spiny neurons of DJ-1-/- mice, but long-term depression (LTD) was absent. The LTD deficit was reversed by treatment with D2 but not D1 receptor agonists. Furthermore, DJ-1-/- mice displayed hypoactivity in the open field. Collectively, our findings suggest an essential role for DJ-1 in dopaminergic physiology and D2 receptor-mediated functions. [Copyright &y& Elsevier]

Abstract: Long- and short-term changes in the efficacy of synaptic transmission are known as synaptic plasticity. Phenomena such as long-term depression (LTD) and long-term potentiation (LTP) are two classical forms of synaptic plasticity that are expressed in several brain areas, including the striatum. Bi-directional changes in corticostriatal synaptic transmission, i.e. LTD and LTP, have been proposed to represent the cellular mechanisms underlying the physiological processes of motor learning and behavior. In parallel, other forms of synaptic plasticity induced by different experimental pathological conditions have been described in the striatum; these changes are presumed to represent the cellular processes underlying several neurological disorders, including Parkinson''s disease and Huntington''s chorea. A considerable number of receptor and post-receptor systems participate in the mechanisms of synaptic plasticity in the striatum, where glutamate plays a primary role through its ionotropic and metabotropic receptors (mGluRs). These latter constitute a group of recently characterized molecules, which have been shown to modulate synaptic transmission by acting on cellular excitability, ionic conductances and neurotransmitter release. These receptors have also been involved in several neuronal pathophysiological processes. The role of mGluRs in synaptic transmission and synaptic plasticity has been recently deeply studied and characterized in the striatum, in both physiological and pathological conditions. These findings open new and interesting perspectives in the study of basal ganglia function, and introduce new possible pharmacological approaches for the treatment of neurological disorders in which mGluRs have been experimentally involved. [Copyright &y& Elsevier]

Purpose: Alterations in neuronal calcium (Ca2+) homeostasis are believed to play an essential role in the generation and propagation of epileptiform events. Levetiracetam (LEV) and lamotrigine (LTG), novel antiepileptic drugs (AEDs), were tested on epileptiform events and the corresponding elevations in intracellular Ca2+ concentration ([Ca2+]i) recorded from rat neocortical slices. Methods: Electrophysiological recordings were performed from single pyramidal neurons from a slice preparation. Spontaneous epileptiform events consisting of long-lasting, repetitive paroxysmal depolarization shifts (PDSs) and interictal spike activity were induced by reducing the magnesium concentration from the solution and by adding bicuculline and 4-aminopyridine. Simultaneously, microfluorimetric measurements of [Ca2+]i were performed. Optical imaging with Ca2+ indicators revealed a close correlation between Ca2+ transients and epileptiform events. Results: Both LEV and LTG were able to reduce both amplitude and duration of PDSs, as well as the concomitant elevation in [Ca2+]i, in a dose-dependent fashion. Whole-cell patch-clamp recordings from isolated neocortical neurons revealed that LEV significantly reduced N-, and partially P/Q-type high-voltage-activated (HVA) Ca2+ currents, whereas sodium currents were unaffected. Interestingly, the inhibitory effects of LEV were mimicked and occluded by LTG or by a combination of ω-conotoxin GVIA and ω-agatoxin IVA, selective blockers of N- and P/Q-type HVA channels, respectively, suggesting a common site of action for these AEDs. Conclusions: These results demonstrate that large, transient elevations in neuronal [Ca2+]i correlate to epileptiform discharges. The antagonistic effects of LEV and LTG on [Ca2+]i overload might represent the basis for their anticonvulsant efficacy and could preserve neuronal viability. [ABSTRACT FROM AUTHOR]

Exogenous arginine slows the progression of chronic renal failure (CRF) in remnant rats through a nitric oxide (NO)-dependent mechanism. We tested whether the inhibition of arginase could induce similar results through the increased availability of endogenous arginine. Three groups of remnant rats were studied for 8 wk: 1) untreated rats (REM); 2) remnant rats treated with 1% L-arginine (ARG); and 3) remnant rats administered a Mn[sup 2+]-free diet to inhibit arginase (MNF). Normal rats (NOR) were used as controls. Liver arginase activity was depressed in MNF rats (-35% vs. REM, P < 0.01). No difference in metabolic data was detected among the groups throughout the study; blood pressure was significantly lower in MNF vs. ARG and REM rats after 6 wk (P < 0.001). The glomerular filtration rate (GFR) was greatly depressed in REM rats (-47% vs. NOR, P < 0.03) but was higher in ARG and MNF rats (+40 and +43% vs. REM, respectively, P < 0.05), with comparable changes in renal hemodynamics. Despite the better GFR, proteinuria was decreased in both ARG and MNF rats (-42%, P < 0.05, and -57%, P < 0.01, respectively, vs. REM rats). Arginine plasma levels, significantly reduced in REM rats (-41% vs. NOR, P < 0.01), were partially restored in MNF rats (+ 38% vs. REM), and urinary nitrite excretion, greatly depressed in REM rats (-76% vs. NOR, P < 0.01), was significantly increased in MNF rats (+209% vs. REM, P < 0.05). At the renal level, arginase activity was only slightly depressed in MNF rats (-18% vs. REM), but intrarenal concentrations of arginine were lower in this latter group (P < 0.05 vs. other groups). Beyond the hemodynamic modifications, MNF rats showed a lower glomerular sclerosis index (P < 0.05 vs. REM and ARG). Inhibition of arginase slows the progression of CRF in remnant rats similarly to argininetreated rats; the better histological protection in MNF rats, however, suggests that additional factors are involved in these modifications. [ABSTRACT FROM AUTHOR]

Intracranial hemangiopericytomas are rare tumors, accounting for 1% of all central nervous system malignancies. This tumor is considered at high risk of local and also distant metastases. Surgical excision is the gold standard for treatment, but it is seldom curative by itself. Adjuvant radiotherapy is often recommended. We report an overview and update of the available literature on one such rare but aggressive mesenchymal tumor, using the case of a 46-year-old woman affected by hemangiopericytoma of the cavernous sinus surgically removed and treated with adjuvant radiotherapy at our institution. After seven years, the patient underwent a local recurrence and was treated with exeresis and Gamma Knife radiotherapy. Sixteen years after the initial diagnosis, she is still well with stable disease. [ABSTRACT FROM AUTHOR]

Solitary fibrous tumor (SFT) of the central nervous system, previously named and classified with the term hemangiopericytoma (HPC), is rare and accounts for less than 1% of all intracranial tumors. Despite its benign nature, it has a malignant behavior due to the high rate of recurrence and distant metastasis, occurring in up to 50% of cases. Surgical resection of the tumor is the treatment of choice. Radiotherapy represents the gold standard in the case of post-surgery residual disease, relapse, and distant metastases. In this context, imaging plays a crucial role in identifying the personalized therapeutic decision for each patient. Although the referring imaging approach in SFT is morphologic, an emerging role of positron emission tomography (PET) has been reported in the literature. However, there is still a debate on which radiotracers have the best accuracy for studying these uncommon tumors because of the histological or biological heterogeneity of SFT. [ABSTRACT FROM AUTHOR]

We present the case of a 9-year-old child with lysinuric protein intolerance and Fanconi syndrome. She was referred to our hospital with a persistent metabolic acidosis and polyuria. Renal investigations revealed all laboratory signs of Fanconi syndrome, with glucosuria, generalized aminoaciduria, phosphaturia and severe hypercalciuria. The diagnosis of Fanconi syndrome was confirmed by a renal biopsy that showed extensive lesions of proximal tubular epithelial cells with vacuolation of these cells and a sloughing of the brush border. [ABSTRACT FROM AUTHOR]

Orexin-A is a neuropeptide product of the lateral hypothalamus that acts on two receptors, OX1R and OX2R. The orexinergic system is involved in feeding, sleep, and pressure regulation. Recently, orexin-A levels have been found to be negatively correlated with renal function. Here, we analyzed orexin-A levels as well as the incidence of SNPs in the hypocretin neuropeptide precursor (HCRT) and its receptors, HCRTR1 and HCRTR2, in 64 patients affected by autosomal dominant polycystic kidney disease (ADPKD) bearing truncating mutations in the PKD1 or PKD2 genes. Twenty-four healthy volunteers constituted the control group. Serum orexin-A was assessed by ELISA, while the SNPs were investigated through Sanger sequencing. Correlations with the main clinical features of PKD patients were assessed. PKD patients showed impaired renal function (mean eGFR 67.8 ± 34.53) and a statistically higher systolic blood pressure compared with the control group (p < 0.001). Additionally, orexin-A levels in PKD patients were statistically higher than those in healthy controls (477.07 ± 69.42 pg/mL vs. 321.49 ± 78.01 pg/mL; p < 0.001). Furthermore, orexin-A inversely correlated with blood pressure (p = 0.0085), while a direct correlation with eGFR in PKD patients was found. None of the analyzed SNPs showed any association with orexin-A levels in PKD. In conclusion, our data highlights the emerging role of orexin-A in renal physiology and its potential relevance to PKD. Further research is essential to elucidate the intricate mechanisms underlying orexin-A signaling in renal function and its therapeutic implications for PKD and associated cardiovascular complications. [ABSTRACT FROM AUTHOR]

AbstractCombination of morphological and electrophysiological techniques provided data, suggesting existence in the young rat striatum of a peculiar class of neurons, the neurogliaform or dwarf neurons. Striatal neurons (n = 92), intracellularly recorded from rat brain slices, were filled (one in each slice) with the intracellular marker biocytin, to compare physiological and morphological properties in the same cell. Moreover, some neurons (n = 7) were filled with biocytin plus the fluorescent calcium indicator fura-2, identifying cells during electrophysiological recording. Electrophysiological recordings showed that striatal neurons had different firing patterns, suggestive in most cases (n = 80) of spiny neuron class and in others (n = 12) of interneuron class. Fura-2 injection clearly identified the body of six medium-sized cells and of one distinctive tiny cell. This small cell, however, showed a resting membrane potential and spontaneous and evoked firing pattern characteristic of striatal interneurons. Moreover, the fura-2 injected in such small neuron also completely filled the cell body of a near large neuron; the fura-2 fluorescence changed synchronously in the two paired neurons after electrical stimulation of the impaled small one. Accordingly, the biocytin staining identified the morphology of the small recorded neuron as a neurogliaform-like cell apposed to a dendrite of an aspiny neuron, suggesting that the dye injected in one neuron had diffused to the other of a different type. Furthermore, such heterologous dye coupling unexpectedly involved seven pairs of cells detected with biocytin staining (7.6% of the recorded neurons), invariably represented by a medium or large neuron on one side, and on the other side by a small (5.44 ± 0.15 × 9.14 ± 0.7 μm, mean ± SD; n = 7) neurogliaform cell, roundish in shape with few slender and short processes, usually apposed to a dendrite of the companion neurons (six out of seven). In... [ABSTRACT FROM AUTHOR]

Key Clinical Message: PET‐driven SBRT plus pembrolizumab as first‐line therapy against pleomorphic Pancoast cancer appears beneficial, probably due to high equivalent doses of SBRT on photopenic necrotic core and synergic immune system stimulation of immunoradiotherapy. [ABSTRACT FROM AUTHOR]

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a common monogenic disorder characterized by renal cysts and progressive renal failure. In kidney diseases, adipose tissue undergoes functional changes that have been associated with increased inflammation and insulin resistance mediated by release of adipokines. Adiponectin is involved in various cellular processes, such as energy and inflammatory and oxidative processes. However, it remains to be determined whether adiponectin is involved in the concomitant metabolic dysfunctions present in PKD. In this scenario, we aimed to analyze: (a) PPARγ, ADIPOQ, ADIPOR1 and ADIPOR2 gene variations in 92 ADPKD patients through PCR-Sanger sequencing; and (b) adiponectin levels and its oligomerization state by ELISA and Western Blot. Our results indicated that: (a) 14 patients carried the PPARγ SNP, 29 patients carried the ADIPOQ SNP rs1501299, and 25 patients carried the analyzed ADIPOR1 SNPs. Finally, 82 patients carried ADIPOR2 SNPs; and (b) Adiponectin is statistically lower in ADPKD patients compared to controls, and further statistically lower in ESRD than in non-ESRD patients. An inverse relationship between adiponectin and albumin and between adiponectin and creatinine and a direct relationship between adiponectin and eGFR were found. Interestingly, significantly lower levels of adiponectin were found in patients bearing the ADIPOQ rs1501299 SNP and associated with low levels of eGFR. In conclusion, adiponectin levels and the presence of ADIPOQ rs1501299 genotype are significantly associated with a worse ADPKD phenotype, indicating that both could potentially provide important insights into the disease. Further studies are warranted to understand the pathophysiological role of adiponectin in ADPKD patients. [ABSTRACT FROM AUTHOR]

While neurological manifestations are core features of Fabry disease (FD), quantitative neuroimaging biomarkers allowing to measure brain involvement are lacking. We used deep learning and the brain‐age paradigm to assess whether FD patients' brains appear older than normal and to validate brain‐predicted age difference (brain‐PAD) as a possible disease severity biomarker. MRI scans of FD patients and healthy controls (HCs) from a single Institution were, retrospectively, studied. The Fabry stabilization index (FASTEX) was recorded as a measure of disease severity. Using minimally preprocessed 3D T1‐weighted brain scans of healthy subjects from eight publicly available sources (N = 2160; mean age = 33 years [range 4–86]), we trained a model predicting chronological age based on a DenseNet architecture and used it to generate brain‐age predictions in the internal cohort. Within a linear modeling framework, brain‐PAD was tested for age/sex‐adjusted associations with diagnostic group (FD vs. HC), FASTEX score, and both global and voxel‐level neuroimaging measures. We studied 52 FD patients (40.6 ± 12.6 years; 28F) and 58 HC (38.4 ± 13.4 years; 28F). The brain‐age model achieved accurate out‐of‐sample performance (mean absolute error = 4.01 years, R2 =.90). FD patients had significantly higher brain‐PAD than HC (estimated marginal means: 3.1 vs. −0.1, p =.01). Brain‐PAD was associated with FASTEX score (B = 0.10, p =.02), brain parenchymal fraction (B = −153.50, p =.001), white matter hyperintensities load (B = 0.85, p =.01), and tissue volume reduction throughout the brain. We demonstrated that FD patients' brains appear older than normal. Brain‐PAD correlates with FD‐related multi‐organ damage and is influenced by both global brain volume and white matter hyperintensities, offering a comprehensive biomarker of (neurological) disease severity. [ABSTRACT FROM AUTHOR]

Oxytocin (OT) is a neuropeptide that modulates social-related behavior and cognition in the central nervous system of mammals. In the CA1 area of the hippocampus, the indirect effects of the OT on the pyramidal neurons and their role in information processing have been elucidated. However, limited data are available concerning the direct modulation exerted by OT on the CA1 interneurons (INs) expressing the oxytocin receptor (OTR). Here, we demonstrated that TGOT (Thr4,Gly7-oxytocin), a selective OTR agonist, affects not only the membrane potential and the firing frequency but also the neuronal excitability and the shape of the action potentials (APs) of these INs in mice. Furthermore, we constructed linear mixed-effects models (LMMs) to unravel the dependencies between the AP parameters and the firing frequency, also considering how TGOT can interact with them to strengthen or weaken these influences. Our analyses indicate that OT regulates the functionality of the CA1 GABAergic INs through different and independent mechanisms. Specifically, the increase in neuronal firing rate can be attributed to the depolarizing effect on the membrane potential and the related enhancement in cellular excitability by the peptide. In contrast, the significant changes in the AP shape are directly linked to oxytocinergic modulation. Importantly, these alterations in AP shape are not associated with the TGOT-induced increase in neuronal firing rate, being themselves critical for signal processing. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the role of 18F-fluorocholine ( 18F-FCH) positron emission tomography/computed tomography (PET/CT) in prostate cancer (PC) patients with biochemical recurrence who were submitted to different curative treatments. Methods: Seventy-five patients with PC who underwent 18F-FCH PET/CT for biochemical recurrence were retrospectively analyzed to distinguish patients who were submitted only to prostatectomy (PR group), only to radiotherapy (RT) on prostate with curative intent (RT group), and to both (PR + RT group). Correlations between 18F-FCH PET/CT and outcome and between prostate-specific antigen (PSA) values and sites and the number of metastases were analyzed. The performance of 18F-FCH PET/CT in relation to the PSA value and of maximum standardized uptake value (SUVmax) value in relation to patient outcome were assessed by receiver operating characteristic (ROC) curves. Results: 18F-FCH PET/CT relapses mostly involved lymph nodes, bones, and prostate bed. K-cohen test showed moderate agreement with the outcome in the whole population and in the PR group, whereas in the RT group it was perfect and in PR + RT fair. A statistically significant difference in PSA values was observed in the presence of lymph node metastases and with multiple metastases. ROC curves showed PSA cut-off values of 1.96 ng/dL, 1.95, 1.81, and 2.96, respectively, in the whole population, PR, RT and PR + RT group. SUVmax cut-off values of 3.75, 3.45, and 4.7 were described in the whole population, PR group, and PR + RT group. Conclusion: The study confirms that 18F-FCH PET/CT is still valid in PC patients with suspected biochemical recurrence. Therefore, we can affirm that it still makes sense to perform it both with high PSA values and with lower values when prostate-specific membrane antigen tracers are not available. [ABSTRACT FROM AUTHOR]

Parkinson's Disease (PD) is a neurodegenerative disorder characterized by both motor and non-motor symptoms (NMS). Among NMS, constipation and pain are both highly prevalent and debilitating affecting up to 80% of PD patients and impairing their quality of life. Here, we investigated the relationship between constipation and pain in PD patients. This is a retrospective study assessing the relationship between pain and constipation in a PD patient population from a clinical database of patients attending the outpatient clinic of the movement disorders division, Neurology Unit of Policlinico Tor Vergata, in Rome. Subjects were assessed with the Unified Parkinson's Disease Rating Scale (UPDRS) part III, Hoehn and Yahr (H&Y) stage, King's Parkinson's Disease Pain Scale (KPPS), Brief Pain Inventory (BPI), Non-Motor Symptoms Scale (NMSS) and Beck Depression Inventory (BDI). Patients were further divided in two groups (Group 1, 32 patients with constipation and Group 2, 35 PD patients without constipation) ANOVA and ANCOVA analysis were used to compare the two groups. PD patients with constipation had significantly higher pain severity and pain interference, as measured by the BPI scale and higher total KPPS score, fluctuation-related pain, nocturnal pain, and radicular pain when compared to PD patients without constipation. This study highlights for the first time a possible interplay between constipation and pain in PD that deserves further investigations. [ABSTRACT FROM AUTHOR]

Background: Idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) is associated with prodromal Parkinson's disease (PD), but the mechanisms linking phenoconversion of iRBD to PD have not yet been clarified. Considering the association between mitochondrial dysfunction and sleep disturbances in PD, we explored mitochondrial activity in fibroblasts derived from iRBD patients to identify a biochemical profile that could mark the presence of impending neurodegeneration. Methods: The study involved 28 participants, divided into three groups: patients diagnosed with iRBD, PD patients converted from iRBD (RBD‐PD), and healthy controls. We performed a comprehensive assessment of mitochondrial function, including an examination of mitochondrial morphology, analysis of mitochondrial protein expression levels by western blot, and measurement of mitochondrial respiration using the Seahorse XFe24 analyzer. Results: In basal conditions, mitochondrial respiration did not differ between iRBD and control fibroblasts, but when cells were challenged with a higher energy demand, iRBD fibroblasts exhibited a significant (P = 0.006) drop in maximal and spare respiration compared to controls. Interestingly, RBD‐PD patients showed the same alterations with a further significant reduction in oxygen consumption linked to adenosine triphosphate production (P = 0.032). Moreover, RBD‐PD patients exhibited a significant decrease in protein levels of complexes III (P = 0.02) and V (P = 0.002) compared to controls, along with fragmentation of the mitochondrial network. iRBD patients showed similar, but milder alterations. Conclusions: Altogether, these findings suggest that mitochondrial dysfunctions in individuals with iRBD might predispose to worsening of the bioenergetic profile observed in RBD‐PD patients, highlighting these alterations as potential predictors of phenoconversion to PD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Aim: We investigated the value of serial cardiac 18F-FDG PET-MRI in Anderson–Fabry disease (AFD) and the potential relationship of imaging results with FASTEX score. Methods and results: Thirteen AFD patients underwent cardiac 18F-FDG PET-MRI at baseline and follow-up. Coefficient of variation (COV) of FDG uptake and FASTEX score were assessed. At baseline, 9 patients were enzyme replacement therapy (ERT) naïve and 4 patients were under treatment. Two patients presented a FASTEX score of 0 indicating stable disease and did not show any imaging abnormality at baseline and follow-up PET-MRI. Eleven patients had a FASTEX score > 20% indicating disease worsening. Four of these patients without late gadolinium enhancement (LGE) and with normal COV at baseline and follow-up had a FASTEX score of 35%. Three patients without LGE and with abnormal COV at baseline and follow-up had a FASTEX score ranging from 30 to 70%. Three patients with LGE and abnormal COV at baseline and follow-up had a FASTEX score between 35 and 75%. Finally, one patient with LGE and normal COV had a FASTEX score of 100%. Of the 12 patients on ERT at follow-up, FASTEX score was significantly higher in those 4 showing irreversible cardiac injury at baseline compared to 8 with negative LGE (66 ± 24 vs. 32 ± 21, p = 0.03). Conclusion: 18F-FDG PET-MRI may be effective to monitor cardiac involvement in AFD. [ABSTRACT FROM AUTHOR]

AbstractWe investigated the effects of oxygen (O2)/glucose deprivation on intracellular sodium concentration ([Na+]i) of cortical pyramidal cells in a slice preparation of rat frontal cortex. Intracellular recordings were combined with microfluorometric measurements of [Na+]i using the Na+‐sensitive dye sodium‐binding benzofuran isophthalate (SBFI). Deprivation of O2/glucose caused an initial membrane hyperpolarization that was followed by a slowly developing large depolarization. Levels of [Na+]i started to increase significantly during the phase of membrane hyperpolarization. Neither tetrodotoxin, a combination of ionotropic and metabotropic glutamate receptor antagonists (d‐amino‐phosphonovalerate, 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione plus S‐methyl‐4‐carboxyphenylglycine) nor bepridil, an inhibitor of the Na+/Ca2+‐exchanger, affected these responses to O2/glucose. The present results demonstrate that, in cortical neurons, O2/glucose deprivation induces an early rise in [Na+]i which cannot be ascribed to the activity of voltage gated Na+‐channels, glutamate receptors or of the Na+/Ca2+‐exchanger. [ABSTRACT FROM AUTHOR]

This review examines the impact of childhood obesity on the kidney from an epidemiological, pathogenetic, clinical, and pathological perspective, with the aim of providing pediatricians and nephrologists with the most current data on this topic. The prevalence of childhood obesity and chronic kidney disease (CKD) is steadily increasing worldwide, reaching epidemic proportions. While the impact of obesity in children with CKD is less pronounced than in adults, recent studies suggest a similar trend in the child population. This is likely due to the significant association between obesity and the two leading causes of end-stage renal disease (ESRD): diabetes mellitus (DM) and hypertension. Obesity is a complex, systemic disease that reflects interactions between environmental and genetic factors. A key mechanism of kidney damage is related to metabolic syndrome and insulin resistance. Therefore, we can speculate about an adipose tissue–kidney axis in which neurohormonal and immunological mechanisms exacerbate complications resulting from obesity. Adipose tissue, now recognized as an endocrine organ, secretes cytokines called adipokines that may induce adaptive or maladaptive responses in renal cells, leading to kidney fibrosis. The impact of obesity on kidney transplant-related outcomes for both donors and recipients is also significant, making stringent preventive measures critical in the pre- and post-transplant phases. The challenge lies in identifying renal involvement as early as possible, as it is often completely asymptomatic and not detectable through common markers of kidney function. Ongoing research into innovative technologies, such as proteomics and metabolomics, aims to identify new biomarkers and is constantly evolving. Many aspects of pediatric disease progression in the population of children with obesity still require clarification. However, the latest scientific evidence in the field of nephrology offers glimpses into various new perspectives, such as genetic factors, comorbidities, and novel biomarkers. Investigating these aspects early could potentially improve the prognosis of these young patients through new diagnostic and therapeutic strategies. Hence, the aim of this review is to provide a comprehensive exploration of the pathogenetic mechanisms and prevalent pathological patterns of kidney damage observed in children with obesity. [ABSTRACT FROM AUTHOR]

Neurotensin (NT) is a 13-amino acid peptide acting as a neuromodulator in the CNS. NT immunoreactive cell bodies, synaptic terminals and receptors (NTS) are intimately associated with the dopaminergic system. In fact, NT exerts a stimulatory action on the dopaminergic (DAergic) neurons of substantia nigra pars compacta (SNpc) and ventral tegmental area by activating a mixed cation conductance, reducing D 2 -autoinhibition and modulating NMDA and AMPA transmission. In the present work, we describe an inhibitory effect of NT on metabotropic glutamate receptor I (mGluR I) actions in rat SNpc DAergic neurons. NTS and mGluR I share the same G αq/11 -PLC-IP 3 -Ca2+ intracellular pathway which causes either activation of unspecific cationic conductance or intracellular Ca2+ accumulation. We find that NT inhibits both inward current and the associated intracellular calcium elevation, elicited by the selective mGluR I agonist S-DHPG, in a concentration-dependent manner. This effect is mediated by type 1/2 NT receptors (NTS 1/2), as revealed by pharmacological analysis. Activation of other metabotropic receptors, such as muscarinic and GABA B , does not inhibit mGluR I inward currents. PKC, MEK 1–2, calcineurin, clathrin-dependent endocytosis and intracellular Ca2+ elevation are not involved in the NT-mediated modulation of mGluR I responses. Interestingly, inhibition of G-protein coupled receptor kinases (GRKs) 2/3 exacerbates the NT-induced mGluR I inhibition while sustaining the NT-induced inward current during repeated agonist stimulation. These data suggest that GRKs are key molecules regulating either the NT excitation or the cross-talk between NTS 1/2 and mGluR I in DAergic neurons of rat midbrain by tuning the degree of NTS 1/2 desensitization. Image 1 • Neurotensin (NT) inhibits mGluR I responses in dopaminergic neurons of rat substantia nigra pars compacta. • The NT-mediated inhibition of mGluR I involves NTS 1/2 receptors. • The NT-mediated inhibition of mGluR I is Ca2+-independent and does not involve common Gq-activated intracellular pathways. • NTS 1/2 undergo functional desensitization by G-protein coupled receptor kinases (GRKs) 2/3. • Inhibition of GRKs 2/3 strongly potentiates the NT-mediated inhibition of mGluR I responses. [ABSTRACT FROM AUTHOR]

There is limited evidence on the risk stratification of cardiovascular outcomes in patients with Fabry disease (FD). This study sought to classify FD patients into disease stages, based on the extent of the cardiac damage evaluated by echocardiography, and to assess their prognostic impact in a multicenter cohort. Patients with FD from 5 Italian referral centers were categorized into 4 stages: stage 0, no cardiac involvement; stage 1, left ventricular (LV) hypertrophy (LV maximal wall thickness >12 mm); stage 2, left atrium (LA) enlargement (LA volume index >34 mL/m2); stage 3, ventricular impairment (LV ejection fraction <50% or E/eʹ ≥15 or TAPSE <17 mm). The study endpoint was the composite of all-cause death, hospitalization for heart failure, new-onset atrial fibrillation, major bradyarrhythmias or tachyarrhythmias, and ischemic stroke. A total of 314 patients were included. Among them, 174 (56%) were classified as stage 0, 41 (13%) as stage 1, 57 (18%) as stage 2 and 42 (13%) as stage 3. A progressive increase in the composite event rate at 8 years was observed with worsening stages of cardiac damage (log-rank P < 0.001). On multivariable Cox regression analysis, the staging was independently associated with the risk of cardiovascular events (HR: 2.086 per 1-stage increase; 95% CI: 1.487-2.927; P < 0.001). Notably, cardiac staging demonstrated a stronger and additive prognostic value, as compared with the degree of LV hypertrophy. In FD patients, a novel staging classification of cardiac damage, evaluated by echocardiography, is strongly associated with cardiovascular outcomes and may be helpful to refine risk stratification. [Display omitted] [ABSTRACT FROM AUTHOR]

Introduction: Early -onset Parkinson's disease (EOPD) labels those cases with onset earlier than fifty. Although peculiarities emerged either in clinical or pathological features, EOPD is managed alike typical, late-onset PD. A customized approach would be, instead, better appropriate. Accordingly, a deeper characterization of the clinical course, with an estimation of the disease progression rate, the therapy flow, and the main motor and non-motor complications occurrence, is needed. Methods: A longitudinal cohort of 193 EOPD patients (selected on a single-centre population of 2000 PD cases) was retrospectively analysed, providing descriptive statics on a series of clinical parameters (genetics, phenotype, comorbidities, therapies, motor and non-motor complications, marital and gender issues) and modelling the trajectories from diagnosis to 10 years later of both Hoehn and Yahr (H&Y) stage and levodopa equivalent daily dose (LEDD). Results: EOPD had a prevalence of 9.7%, including few monogenic cases. It mostly appeared as a motor syndrome, with asymmetric, rigid-akinetic presentation. H&Y linearly progressed with an increment of 0.92 points/10 years; LEDD flow had a non-linear trend, increasing of 526.90 mg/day in 0–5 years, and 166.83 mg/day in 5–10 years. Motor fluctuations started 6.5 ± 3.2 years from onset, affecting up to 80% of the cohort. Neuropsychiatric troubles interested the 50%, sexual complaints the 12%. Gender-specific motor disturbances emerged. Conclusion: We shaped EOPD course, modelling a "brain-first" PD subtype, slowly progressive, with non-linear dopaminergic requirement. Major burden mostly resulted from motor fluctuations, neuropsychiatric complications, sexual and marital complaints, with a considerable gender-effect. [ABSTRACT FROM AUTHOR]

Anderson-Fabry disease (AFD) is a rare multisystem X-linked lysosomal storage disorder caused by α-galactosidase A enzyme deficiency. Long-term cardiac involvement in AFD results in left ventricular hypertrophy and myocardial fibrosis, inducing several complications, mainly arrhythmias, valvular dysfunction, and coronary artery disease. Cardiac magnetic resonance (CMR) represents the predominant noninvasive imaging modality for the assessment of cardiac involvement in the AFD, being able to comprehensively assess cardiac regional anatomy, ventricular function as well as to provide tissue characterization. This review aims to explore the role of the most advanced CMR techniques, such as myocardial strain, T1 and T2 mapping, perfusion and hybrid imaging, as diagnostic and prognostic biomarkers. [ABSTRACT FROM AUTHOR]

Background: Cognitive dysfunction is a well-established manifestation of the post-COVID syndrome. Psychological vulnerability to stressors can modify disease trajectories, causing long-term risk for negative outcomes. Nonetheless, how premorbid risk factors and response to stressor affect neuropsychological changes is still incompletely understood. In this study, we explored the impact of psychosocial variables on cognitive functioning in a post-COVID sample. Methods: All subjects were submitted to a comprehensive neuropsychological battery and an assessment of perceived loneliness, post-traumatic stress, and changes in anxiety and depression levels. A social vulnerability index was also calculated. The set of psycho-social variables was reduced to two Principal Component Analysis (PCA) components: distress and isolation. Results: Forty-five percent of individuals showed cognitive impairments, with predominant memory and executive deficits. Post-traumatic stress disorder was clinically relevant in 44% of the sample. Social vulnerability scores of the sample were comparable to those of general population. The individual performance in learning and response initiation/suppression was directly related to distress component, encasing anxiety, stress, and depression measures. Conclusion: These findings suggest that psychosocial assessment of post-COVID patients can detect fragile individuals at risk of cognitive impairments. Dedicated psychological support services may play a useful role in the prevention of post-COVID cognitive dysfunction. [ABSTRACT FROM AUTHOR]